Sonogashira coupling

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In organic chemistry, a Sonogashira coupling is a coupling reaction of terminal alkynes with aryl or vinyl halides. This reaction was first reported by Kenkichi Sonogashira and Nobue Hagihara in 1975.[1]

Sonogashira coupling

Contents

[edit] Catalyst

Typically, two catalysts are needed for this reaction: a zerovalent palladium complex and a halide salt of copper(I). The palladium complex activates the organic halides by oxidative addition into the carbon-halogen bond. Phosphine-palladium complexes such as tetrakis(triphenylphosphine)palladium(0) are used for this reaction, but palladium(II) complexes are also available because they are reduced to the palladium(0) species by the consumption of terminal alkynes in the reaction medium. In contrast, copper(I) halides react with the terminal alkyne and produce copper(I) acetylide, which acts as an activated species for the coupling reactions.

[edit] Conditions

The reaction medium must be basic to neutralize the hydrogen halide produced as the byproduct of this coupling reaction, so alkylamine compounds such as triethylamine and diethylamine are sometimes used as solvents, but also DMF or ether can be used as solvent. In addition, deaerated conditions are formally needed for Sonogashira coupling reactions because the palladium(0) complexes are unstable in the air, and oxygen promotes the formation of homocoupled acetylenes. Recently, development of air-stable organopalladium catalysts enable this reaction to be conducted in the ambient atmosphere.

[edit] Mechanism

The Sonogashira coupling is a modification of the Castro-Stephens coupling with added palladium and in situ preparation of the copper acetylide. The reaction mechanism is not clearly understood but in the textbook mechanism revolves around a palladium cycle and a copper cycle.[2]

Sonogashira reaction mechanism

The palladium cycle:

  • The active palladium catalyst is the 14 electron compound Pd(0)L2 A which reacts with the aryl halide or triflate in an oxidative addition to Pd(II) complex B
  • This complex reacts in a rate limiting transmetallation with the copper acetylide produced in the copper cycle to complex C expelling the copper halide CuX.
  • Both organic ligands are trans oriented and convert to cis in a trans-cis isomerization to complex D
  • In the final step the product is released in a reductive elimination with regeneration of Pd(0)

The copper cycle:

  • The main limitation of this mechanism is its inability to account for deprotonation of a the terminal alkyne: The employed amines such as diethylamine or N,N-diisopropylethylamine are simply not basic enough. It is suggested that deprotonation is still possible after initial formation of a pi-alkyne complex E
  • The organocopper compound F forms after reaction with the base and continues to react with palladium intermediate B with regeneration of copper halide.
  • The copper acetylide is assumed to be involved in the reduction of Pd(II) catalysts, first forming a dialkyne-PdL2 complex and then by reductive elimination Pd(0) and a diacetylene.
  • A side reaction is a Glaser coupling of two acetylene units.
  • Copper free reactions also exist making the reaction mechanism even more intractable. It is however reported that palladium catalysts can be contaminated by copper salts.

[edit] Scope

Typical reagents and reaction conditions are copper(I) iodide, N,N-diisopropylethylamine, tetrakis(triphenylphosphine)palladium(0) and dimethylformamide,[3] or copper(I) iodide, diethylamine, and dichlorobis(triphenylphosphine)palladium(II)[4]

The Sonogashira coupling is applied in synthesis of cross-conjugated oligo(phenylene enynylene)s[5] and phenanthroline derivatives.[6]

[edit] References

  1. ^ K. Sonogashira, Y. Tohda, N. Hagihara (1975). "A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines". Tetrahedron Letters 16 (50): 4467-4470. doi:10.1016/S0040-4039(00)91094-3. 
  2. ^ The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry Rafael Chinchilla and Carmen Nájera Chem. Rev.; 2007; 107(3) pp 874 - 922; (Review) doi:10.1021/cr050992x
  3. ^ Andrew G. Myers and Peter S. Dragovich (1998). "Synthesis of functionalized enynes by palladium/copper-catalyzed coupling reactions of acetylenes with (Z)-2,3-dibromopropenoic acid ethyl ester: (Z)-2-bromo-5-(trimethylsilyl)-2-penten-4-ynoic acid ethyl ester". Org. Synth.; Coll. Vol. 9: 117. 
  4. ^ James A. Marshall and Clark A. Sehon (2004). "Isomerization of β-alkynyl allylic alcohols to furans catalyzed by silver nitrate on silica gel: 2-Pentyl-3-methyl-5-heptylfuran". Org. Synth.; Coll. Vol. 10: 599. 
  5. ^ Joon Cho, Yuming Zhao, and Rik R. Tykwinski Arkivoc (NZ-1369J) pp 142-150 2005 Online Article
  6. ^ 3-(2,5-Diethyl-4-iodo-phenylethynyl)-[1,10]-phenanthroline Davood Habibi Molbank 2005, M421 Online Article